6haz
Crystal structure of the bromodomain of human SMARCA2 in complex with SMARCA-BD ligand
Structural highlights
Disease[SMCA2_HUMAN] Defects in SMARCA2 are the cause of Nicolaides-Baraitser syndrome (NCBRS) [MIM:601358]. A rare disorder characterized by severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints and broad distal phalanges. Some of the features are progressive with time.[1] [2] Function[SMCA2_HUMAN] Transcriptional coactivator cooperating with nuclear hormone receptors to potentiate transcriptional activation. Also involved in vitamin D-coupled transcription regulation via its association with the WINAC complex, a chromatin-remodeling complex recruited by vitamin D receptor (VDR), which is required for the ligand-bound VDR-mediated transrepression of the CYP27B1 gene. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a post-mitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to post-mitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth (By similarity).[3] Publication Abstract from PubMedTargeting subunits of BAF/PBAF chromatin remodeling complexes has been proposed as an approach to exploit cancer vulnerabilities. Here, we develop proteolysis targeting chimera (PROTAC) degraders of the BAF ATPase subunits SMARCA2 and SMARCA4 using a bromodomain ligand and recruitment of the E3 ubiquitin ligase VHL. High-resolution ternary complex crystal structures and biophysical investigation guided rational and efficient optimization toward ACBI1, a potent and cooperative degrader of SMARCA2, SMARCA4 and PBRM1. ACBI1 induced anti-proliferative effects and cell death caused by SMARCA2 depletion in SMARCA4 mutant cancer cells, and in acute myeloid leukemia cells dependent on SMARCA4 ATPase activity. These findings exemplify a successful biophysics- and structure-based PROTAC design approach to degrade high profile drug targets, and pave the way toward new therapeutics for the treatment of tumors sensitive to the loss of BAF complex ATPases. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design.,Farnaby W, Koegl M, Roy MJ, Whitworth C, Diers E, Trainor N, Zollman D, Steurer S, Karolyi-Oezguer J, Riedmueller C, Gmaschitz T, Wachter J, Dank C, Galant M, Sharps B, Rumpel K, Traxler E, Gerstberger T, Schnitzer R, Petermann O, Greb P, Weinstabl H, Bader G, Zoephel A, Weiss-Puxbaum A, Ehrenhofer-Wolfer K, Wohrle S, Boehmelt G, Rinnenthal J, Arnhof H, Wiechens N, Wu MY, Owen-Hughes T, Ettmayer P, Pearson M, McConnell DB, Ciulli A Nat Chem Biol. 2019 Jun 10. pii: 10.1038/s41589-019-0294-6. doi:, 10.1038/s41589-019-0294-6. PMID:31178587[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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